Solid-state packing dictates the unexpected solubility of aromatic peptides.

Area of Science:

• Biochemistry
• Structural Biology
• Peptide Science

Background:

• Biomolecule solubility and aggregation prediction remain challenging.
• Short aromatic tripeptides are typically highly aggregative.

Purpose of the Study:

• To investigate the molecular basis for the unexpected high solubility of Ala-Phe-Ala (AFA).
• To explore the solubility, aggregation propensity, and atomic-level structure of AFA.

Main Methods:

• Solubility measurements.
• Aggregation propensity assessment.
• Single crystal X-ray diffraction for structural analysis.

Main Results:

• AFA demonstrated exceptionally high water solubility, reaching 672 mM.
• The crystal structure revealed an anti-parallel β-sheet conformation.
• No aromatic interactions were observed in the crystal structure, contrasting with typical peptide aggregation.

Conclusions:

• The anti-parallel β-sheet structure lacking aromatic interactions explains AFA's high solubility.
• This study provides mechanistic insights into peptide solubility.
• A simple tool for solubility estimation is suggested, with implications for peptide drug design and nanotechnology.